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Synthesis of 2-fluoro-substituted and 2,6-modified purine 2',3'-dideoxy-2',3'-difluoro-d-arabinofuranosyl nucleosides from d-xylose.

ABSTRACT: A series of novel purine-modified 2',3'-dideoxy-2',3'-difluro-D-arabinonucleosides, including fluorinated analogs of fludarabine and nelarabine, have been prepared via anion glycosylation reactions of salts of 2-fluoropurine derivatives with the glycosyl bromide. A short and efficient synthetic route to the carbohydrate precursor 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranosyl bromide was developed in five steps from d-xylose. Improved synthesis of methyl 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranoside based upon the study of diethylaminosulfur trifluoride (DAST)-reactions with 5-O-protected methyl D-xylosides was explored using mild reaction conditions on the key step. New peculiarities for selective fluorinations of 5-O-benzoylated α- and β-D-pentofuranosides with DAST leading to the formation of mono and difluoro-furanoside derivatives are reported.

SUBMITTER: Sivets GG

PROVIDER: S-EPMC8313018 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Synthesis of 2-fluoro-substituted and 2,6-modified purine 2',3'-dideoxy-2',3'-difluoro-d-arabinofuranosyl nucleosides from d-xylose.

Sivets Grigorii G GG Amblard Franck F Schinazi Raymond F RF

Tetrahedron 20190216 13

A series of novel purine-modified 2',3'-dideoxy-2',3'-difluro-D-arabinonucleosides, including fluorinated analogs of fludarabine and nelarabine, have been prepared via anion glycosylation reactions of salts of 2-fluoropurine derivatives with the glycosyl bromide. A short and efficient synthetic route to the carbohydrate precursor 5-<i>O</i>-benzoyl-2,3-difluoro-α-d-arabinofuranosyl bromide was developed in five steps from d-xylose. Improved synthesis of methyl 5-<i>O</i>-benzoyl-2,3-difluoro-α-d ...[more]

PMID: 34316083

Similar Datasets

Synthesis and antiviral evaluation of 2',3'-dideoxy-2',3'-difluoro-D-arabinofuranosyl 2,6-disubstituted purine nucleosides.

Project description:The synthesis of new 2,6-disubstituted purine 2',3'-dideoxy-2',3'-difluoro-D-arabino nucleosides is reported. Their ability to block HIV and HCV replication along with their cytotoxicity toward Huh-7 cells, human lymphocyte, CEM and Vero cells was also assessed. Among them, β-2,6-diaminopurine nucleoside 25 and guanosine derivative 27 demonstrate potent anti-HIV-1 activity (EC50 = 0.56 and 0.65 μM; EC90 = 4.2 and 3.1 μM) while displaying only moderate cytotoxicity in primary human lymphocytes.

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5-(4-Fluoro-phen-yl)-2-furylmethyl N-(2,6-difluoro-benzo-yl)carbamate.

Project description:The title compound, C(19)H(12)F(3)NO(4), was synthesized by the reaction of 5-(4-fluoro-phen-yl)-2-furan-methanol and 2,6-difluoro-benzoyl-isocyanate. The seven atoms of the fluorophenyl group are disordered over two positions with site occupancy factors ca 0.6 and 0.4. The dihedral angle between the furan and fluorophenyl rings is 1.58°. In the crystal structure, the mol-ecules are linked via inter-molecular N-H⋯O hydrogen bonds to form chains.

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N-[3,5-Dichloro-4-(1,1,2,2-tetra-fluoro-eth-oxy)phen-yl]-2,6-difluoro-benzamide.

Project description:In the title compound, C(15)H(7)Cl(2)F(6)NO(2), the conformation of the N-H bond in the amide segment is anti to the C=O bond and the dihedral angle between the two benzene rings is 78.6 (3)°. The terminal -CHF(2) group is disordered over two orientations in a 0.67:0.33 ratio. In the crystal, the mol-ecules are linked by N-H⋯O hydrogen bonds, generating C(4) chains propagating in [100].

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Adamantane-Substituted Purine Nucleosides: Synthesis, Host–Guest Complexes with β-Cyclodextrin and Biological Activity

Project description:Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host–guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity.

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2,6-Difluoro-benzoic acid.

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(4-Chloro-2-fluoro-phen-yl)[1-(2,6-difluoro-phen-yl)but-3-en-yl]amine.

Project description:In the mol-ecule of the title homoallylic amine, C(16)H(13)ClF(3)N, the dihedral angle between the two benzene rings is 84.63 (4)°. Weak intra-molecular N-H⋯F hydrogen bonds generate S(6) and S(5) ring motifs. In the crystal structure, weak inter-molecuar N-H⋯F hydrogen bonds link mol-ecules into centrosymmetric dimers which are arranged in mol-ecular sheets parallel to the ac plane.

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D- and L-2',3'-didehydro-2',3'-dideoxy-3'-fluoro-carbocyclic nucleosides: synthesis, anti-HIV activity and mechanism of resistance.

Project description:Introducing 2'-fluoro substitution on the 2',3'-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents, D- and L-2',3'-unsaturated 3'-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesized L-series nucleosides, compounds 18, 19, 26 and 28 exhibited moderate antiviral activity (EC50 7.1 microM, 6.4 microM, 10.3 microM, and 20.7 microM, respectively), while among the D-series, the guanosine analogue (35, D-3'-F-C-d4G) exhibited the most potent anti-HIV activity (EC50 0.4 microM, EC90 2.8 microM). However, the guanosine analogue 35 was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen-bonding stabilize the binding of compound 35 in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case of L-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance of D-3'-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184V interaction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the D-guanine derivative 35.

| S-EPMC2533426 | biostudies-literature

N-{[2,5-Dichloro-4-(1,1,2,3,3,3-hexa-fluoro-prop-oxy)phen-yl]amino-carbon-yl}-2,6-difluoro-benzamide.

Project description:In the mol-ecule of the title compound, C(17)H(8)Cl(2)F(8)N(2)O(3), the two aromatic rings are oriented at a dihedral angle of 50.12?(3)°. Intra-molecular N-H?O, C-H?O and N-H?Cl hydrogen bonds result in the formation of two six- and one five-membered rings. The six-membered rings have flattened-boat conformations, while the five-membered ring adopts an envelope conformation. In the crystal structure, inter-molecular N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers.

| S-EPMC2960696 | biostudies-literature

3-Diethyl-carbamoyl-2',4'-difluoro-biphenyl-4-yl 2,6-dichloro-5-fluoro-pyridine-3-carboxyl-ate.

Project description:In the title compound, C(23)H(17)Cl(2)F(3)N(2)O(3), the mol-ecular conformation is significantly strained: atoms O, C(=O) and C attached to the central benzene ring deviate from its plane by 0.118 (2), 0.139 (2) and 0.174 (2) Å, respectively. In the crystal, weak C-H⋯O inter-actions link the mol-ecules into chains along [110]. The crystal packing exhibits short inter-molecular Cl⋯F [2.9840 (16) Å] and Cl⋯Cl [3.2957 (12) Å] contacts.

| S-EPMC3393315 | biostudies-literature

Aromatic Nonpolar Nucleosides as Hydrophobic Isosteres of Pyrimidine and Purine Nucleosides.

Project description:Described are the design, synthesis, and structures of three nonpolar nucleoside isosteres to be used as probes of noncovalent bonding in DNA and as isosteric replacements for the natural nucleosides in designed nucleic acid structures. Reaction of substituted aryl Grignards with 3',5'-bis-O-toluoyl-α-deoxyibofuranosyl chloride and subsequent deprotection with sodium methoxide in methanol afforded the two β-C-nucleoside pyrimidine analogs 1 and 2. The dimethylindolyl nucleoside 3, a purine isostere, was obtained by a nucleophilic displacement on α-chlorodeoxyribofuranose by the sodium salt of 4,6-dimethylindole, followed by deprotection. Regio- and stereochemistry of the products were established with NOE difference spectra and (1)H NMR splitting patterns. Analogs 1 and 2 are nonpolar isosteres of thymidine, and nucleoside 3 is an isostere of 2-aminodeoxyadenosine, the triply-bonded Watson-Crick partner of thymidine. Semiempirical AM1 calculations were carried out to provide bond length information to assess structural similarities between the isosteres and their natural counterparts.

| S-EPMC2946157 | biostudies-literature

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